Aldolization

The reaction of aldolization or reaction aldol is a reaction of important formation of connections carbon-carbon in Organic chemistry. It generally implies the nucleophilic Addition of a énolate on a Aldéhyde, to form a β-hydroxycétone or Aldol ( ald ehyde + alco ''' ol '''), a structural unit present in many natural molecules and drugs. Sometimes, the additive aldol loses a water molecule during the reaction, to form then a Cétone α, β- unsaturated. This process is called crotonisation , and the reaction in entirety (aldolization + crotonisation) is it called Condensation aldol. This can take place in particular when the finished product is particularly stable.

The reaction aldol was independently discovered by Charles-Adolphe Wurtz and Alexandre Porfirievitch Borodine in 1872. Borodine observed the dimerisation. The reaction of aldolization is used with large scales in the production of chemicals such as the Pentaerythritol and in the Drug company for obtaining optically pure products . For example, the initial way of synthesis of Pfizer for the drug Lipitor (Atorvastatine) approved in 1996 employed two reactions aldol.

The structure aldol is particularly frequent in the Polycétide S, a category of natural products from which many drugs are derived. Those include/understand inter alia the Immunosuppresseur Tacrolimus, the Antibiotique Tétracycline and the Antifongique Amphotéricine B. Considerable research on the reaction aldol allowed the development of effective methods for the synthesis in laboratory, otherwise hardue, of many polycétides. This is important because much of polycétides, just as of other biologically active molecules, meet in nature only in too negligible quantities for a thorough research. The synthesis the many ones of these compounds, regarded a time as quasi-impossible, can now be usually carried out on a laboratory scale, and approaches economic viability in certain cases, like the Discodermolide, a highly active antitumor agent. In Biochemistry, the reaction of aldolization is also a stage-key of the Glycolyse, during which it is catalyzed by Enzyme S called Aldolase S.

The reaction of aldolization is particularly important in organic synthesis because it gives products having two new (on carbons α and β of produced aldol, marked by asterisks on the image higher). Recent methods allow from now on the relative and absolute control of these centers. This is of important very particular in the synthesis of drugs, since of the same molecules structure but of different stereochemistries often have chemical and biological properties different.

A large variety of Nucléophile S different can be employed for the reaction of aldolization, including the énol S, énolate S, aldehydes and quantity of others carbonyl compounds. The électrophile is generally an aldehyde, but of many variations exist, such as for example the Réaction of Mannich. When the nucleophilic one and the électrophile is different (majority of the cases), the reaction is called a cross reaction aldol , contrary to the Dimère S formed in a .

Mechanism

The reaction aldol can be done by the means of two basically different mechanisms. The carbonyl compounds, the such aldehydes and ketones, can be transformed into énols or ethers of énol. These compounds, being nucleophilic on the level of carbon α, can attack the protonic carbonyls particularly reactive such as protonic aldehydes. This is the mechanism of the énol type.

The carbonyl compounds, being, can also be déprotonés to form énolates, which are much nucleophilic than the énols or ethers of énol and can of this fact of attacking électrophiles directly. The électrophiles are generally aldehydes, since the ketones are less reactive. This is the mechanism of the énolate type.

If the conditions of reaction are particularly hard (for example: NaOMe, MeOH, heating with backward flow), condensation can take place. This can usually be avoided by the use of less strong reagents and soft temperatures (example: LDA , THF , -78°C). Although the aldol addition is generally almost complete, this reaction is not irreversible, since the treatment of aldols with strong bases can generally give place to the opposite reaction (and to give again the starting reagents). Condensations aldols are, as for them, irreversible.

Mechanism in acid medium

When an acid catalyst is used, the first stage of the reactional mechanism will be the tautomerization of the function carbonyl in the énol, catalyzed by the acid. The acid is also used to activate the function carbonyl of a another molecule by Protonation, returning it more électrophile. The énol is the Nucléophile, on the level of carbon α. It will be able to attack the molecule carrying the function carbonyl activated, which will give aldol after a Déprotonation. This aldol generally will lose a water molecule to give the unsaturated carbonyl compound (crotonisation).

Mechanism of the reaction aldol in acid catalysis

Mechanism of the crotonisation of an aldol in acid catalysis

In basic medium

If the catalyst is a base of average force a such ion Hydroxyde (

HO^-

) or Alkoxyde (

RO^-

), the reaction aldol will be done via nucleophilic attack of the énolate stabilized by resonance on the grouping carboxyl of another molecule. The formed product will be the alkoxyde of final aldol. Aldol itself is then formed, and it can carry out the crotonisation to give the unsaturated carbonyl compound. The following image shows the mechanism of the reaction of an aldehyde with itself, in basic catalysis.

Mechanism of the reaction aldol in basic catalysis (with ⁻OCH₃ as bases)

Mechanism of the crotonisation of an aldol in basic catalysis (sometimes written in only one stage)

Even if only a basic catalytic quantity is necessary in certain cases, the usual method asks for the use of a stoechiometric quantity of a strong base such LDA. Consequently, the formation of the énolate becomes irreversible, and aldol is not obtained before the Alkoxyde was not protonic at the time of.

References

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